Compositions and methods of treating immediate hypersensitivity reactions with thiazolyl oxamic acid derivatives

ABSTRACT

Anti-allergic agents of aromatic and heterocyclic oxamic acid derivation present the following formula: ##STR1## in which A is a member selected from the group consisting of 2-thiazolyl, 2-pyridyl, 2-pyridyl-N-oxide, 6-(lower)alkyl-2-pyridyl, 3-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkoxy, hydroxy(lower)-alkoxy, 2-(lower alkoxy oxalyloxy) ethoxy, benzyloxy, N-mono- and di-lower alkylamino(lower)-alkoxy, halo, sulfamyl, polyhalo(lower)alkyl, carbamyl, N-lower alkylcarbamyl, nitro, mono- and di-lower alkylamino, phenylazo, carboxy, lower alkylcarbonyl, cyano, carb(lower)alkoxy, phenoxy(lower)alkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidophenoxy radicals; B, when taken alone, is a member selected from the group consisting of --OH, lower alkoxy, --NH 2 , --NHOH, cyclohexyloxy and phenoxy; and 
     Y is a member selected from the group consisting of oxygen and when taken with B and the carbon atom to which they are attached, forms the moiety ##STR2##

RELATED APPLICATIONS

This is a division of application Ser. No. 542,465, filed Jan, 20, 1975,now U.S. Pat. No. 3,966,965, which is a continuation-in-part of Ser. No.344,466, filed Mar. 23, 1974, now abandoned.

BACKGROUND OF THE INVENTION

Atopic immediate sensitivity is the chief manifestation found in animalssuffering from bronchial asthma, seasonal pollinosis (e.g. hay fever),allergic rhinitis, urticaria, allergic conjunctivitis, food allergiesand anaphylactoid reactions. The substances most frequently responsiblefor clinically manifest sensitivities are plant pollen, animal feathersand danders, dust, milk and wheat, whether inhaled or ingested.

Atopic hypersensitivity is found in man, dog and other animals. Itsoccurrance is exceptionally found in the lower animals.

The presence of antibodies associated with atopic hypersensitivityreactions in the host serum is established by the passive sensitizationof the skin of a normal recipient, after injection of serum from asensitized host into a skin site followed by injection of antigen intothe same area 24 hours later, resulting in a local hive. This iscommonly referred to as the Prausnitz-Kustner (P-K) reaction.

The antibody associated with atopic hypersensitivity possessesdistinctive features in that it does not in all forms precipitate withits antigen, fails to pass the placenta from mother to fetus, hasspecial affinity for the skin, frequently lacks specificity toward anindividual antigenic factor and is usually labile at about 56° C. after2 hours.

The homocytotropic antibody found in or induced in the rat is related infunction and reaction to immunoglobulin E (reagin or IgE) found in thehuman. The correlation between homocytotropic antibody in the rate andIgE in the human has been established through the common effectsobtained from chemical reactions, immunological reactions and drugresponses in the two species hosting those antibodies. In the human,reagin is the antibody responsible for atopic immediate hypersensitivereactions. In the rat, the homocytotropic antibody is responsive foratopic immediate hypersensitive reactions.

In theory, reagin, influences the cell membrane of a mast cell byreacting with an antigen, to initiate the reaction(s) within the mastcell which ultimately releases a mediator such as Bradykinin, SRS-A(slow reacting substance-A), histamine and other unknown substances. Themediator effects a change in surrounding cell wall permeabilitypermitting a rapid change in flow or exudance of mediator(s) from thecells, resulting in an allergic attack symptom. The various methodscommonly employed to relieve the symptoms of allergic attack, none ofwhich are considered to be quite acceptable, are to (1) avoid attack bythe antigen, (2) block the production of antibody with animmunosuppressant, (3) block the action of the mediators on the cellunder attack by administration of anti-histaminics,anti-5-hydroxy-tryptamines(5-HT) or anti-inflammatories, or (4)stimulate the cell under attack to negate the action of the mediatorthrough the action of bronchodilators such as Isoprel® or a Xanthine.

The only compound known to data to operate as an anti-allergic byblocking reaction(s) within the mast cells, thereby preventing theproduction and release of mediators, is disodium cromoglycate (INTAL®).

Derivatives of oxamic acids have been employed in the past asintermediates for polymer formation and as tools for chemical research.Each of the known oxamic acid derivatives included as part of the newuse aspect of this application is accompanied with a reference citationin the working examples, infra.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a process forpreventing the release of pharmacological mediators from an immediatehypersensitivity reaction between reaginic type antibodies and anantigen, thereby preventing the symptoms manifest in bronchial asthma,seasonal pollinosis, allergic rhinitis, urticaria, allergicconjunctivities, food allergy and anaphylactoid reactions of asensitized animal, which comprises prophylactically administering tosaid animal an effective amount of a compound of the formula: ##STR3##in which A is a member selected from the group consisting of2-thiazolyl; 2-pyridyl, 2-pyridyl-N-oxide, 3-(lower)alkyl-2-pyridyl,6-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl,α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl, and substitutedphenyl moieties containing from one to three substituents in any of the2,3,4 and 5 positions of the phenyl ring, independently selected fromthe group consisting of lower alkyl, lower alkylthio, loweralkylsulfinyl, lower alkoxy, hydroxy(lower)-alkoxy, 2-(lower alkoxyoxalyloxy) ethoxy, benzyloxy, N-mono-and di-lower alkylaminoalkoxy,halo, sulfamyl, polyhalo(lower)alkyl, carbamyl, N-lower alkylcarbamyl,nitro, mono-and di-lower alkylamino, phenylazo, carboxy, loweralkylcarbonyl, cyano, carb(lower)alkoxy, phenoxy(lower)alkoxy, loweralkoxyoxalamido and lower alkoxyoxalamidophenoxy radicals;

B, when taken alone, is a member selected from the group consisting of--OH, lower alkoxy, --NH₂, --NHOH, cyclohexyloxy and phenoxy; and

Y is a member selected from the group consisting of oxygen and whentaken with B and the carbon atom to which they are attached, forms themoiety ##STR4## The preferred method aspect of this invention comprisesadministering to a sensitized animal a compound which, in minimal dosagequantity, will suppress the allergic response to a degree of or inexcess of 75 percent of the characteristic wheal size of sensitized skintissue, which compounds present the structural formula: ##STR5## inwhich A is a 2-thiazolyl, 2-pyridyl, 3-methyl-2-pyridyl,2-pyridyl-N-oxide, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl,α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl or substituted phenylmoiety containing from one to three substituents, in any of the 2,3,4and 5 positions of the phenyl ring, independently selected from thegroup consisting of lower alkyl, fluoro, lower alkoxy,hydroxy(lower)alkoxy, N-mono- or di(lower)alkylamino(lower)alkoxy,(lower)alkylthio, carbamyl, carb(lower)alkoxy, 2-(lower alkoxyoxalyloxy)ethoxy, trifluoromethyl, nitro, (lower)-alkoxyoxalamido andphenoxy(lower)alkoxy radicals

B, when taken alone, is lower alkoxy, and

Y, when taken alone, is oxygen and when taken with B and the carbon atomto which they are attached forms the moiety ##STR6##

The novel aromatic and heterocyclic oxamic acid derivatives form anadditional aspect of this invention.

The aromatic oxamic acid derivatives present the formula: ##STR7## inwhich R is a member selected from the group consisting of --OH, loweralkoxy, cyclohexyloxy, phenoxy, and amino radical; and

A is a member selected from the group consisting of 2-cyano-phenyl,3-fluorophenyl, 4-phenylazophenyl, 4-carbamylphenyl,2-nitro-4-trifluoromethylphenyl, 2-cyano-3-methoxyphenyl,4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamoylphenyl and ##STR8##wherein R¹ is a member selected from the group consisting of hydroxyl,lower alkyl, lower alkoxy, lower alkylamino and amino radicals;

R² is a member selected from the group consisting of hydrogen, loweralkoxy, hydroxy(lower)alkoxy, N-mono- and di-loweralkylamino(lower)alkoxy, halo, phenoxy(lower)alkoxy, 2-(lower alkoxyoxalyloxy)-ethoxy, benzyloxy, lower alkylthio, and lower alkyl sulfinyl;

R³ is a member selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, halo and nitro; and

R⁴ is a member selected from the group consisting of hydrogen, loweralkyl and lower alkoxy; with the proviso that one of R², R³ and R⁴ mustbe other than hydrogen.

Of the described aromatic oxamic acid derivatives, the preferredaromatic compound aspect of this invention embraces those novelcompounds reducing the wheal and flare manifestation in the tissue of asensitive animal in an amount equal to or greater than 75 percent of theallergic response. Those compounds present the following structuralformula: ##STR9## in which R is lower alkoxy; and

A is a member selected from the group consisting of 3-fluorophenyl,2-cyano-3-methoxyphenyl, 4-nitro-3-trifluoromethylphenyl,5-chloro-2-sulfamoylphenyl and ##STR10## wherein R² is a member selectedfrom the group consisting of hydrogen, lower alkoxy di(lower)alkylamino(lower)-alkoxy, hydroxy(lower)alkoxy, phenoxy(lower)alkoxy and loweralkylthio radicals;

R³ is a member selected from the group consisting of hydrogen, loweralkyl, 2-(lower alkoxy oxalyloxy)-ethoxy, and lower alkoxy radicals;

R⁴ is a member selected from the group consisting of --H, lower alkyland lower alkoxy with the proviso that one of R², R³ and R⁴ must beother than hydrogen.

The novel heterocyclic oxamic acid derivatives of this invention are ofthe formula: ##STR11## in which A is a member selected from the groupconsisting of 2-pyridyl-N-oxide, 6-methyl-2-pyridyl, 3-cyano-2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl, and

R is lower alkoxy.

The term "lower" used throughout this application to modify alkyl,alkoxy, and the like, is intended to embrace univalent aliphatichydrocarbon radicals containing from 1 to 6 carbon atoms, The term"halo" is used to embrace chlorine, bromine, iodine and fluorine.

Each of the compounds disclosed in this application has beendemonstrated to relieve atopic allergic manifestations, whenadministered intraperitoneally to sensitized rats. Several of thecompounds tested were found to be effective anti-allergy agents whenadministered orally to the sensitized animals.

The technique employed to establish the anti-allergic activity of thedisclosed compounds is reported in Immunology, vol. 16, pp. 749-760(1969) and involves four male Charles River rats (200-250 grams bodyweight) per group to provide a control, a host for administration of astandard anti-allergic compound (disodium cromoglycate) and animals forthe test compound. The rats were injected intracutaneously on theirshaved backs with sera from rats immunized with egg albumin andpertussis vaccine. Twenty-four hours after the initial injections, thetest compound is administered intraperitoneally or orally at a dosagelevel of 200 milligrams per kilogram host body weight. Five minuteslater one milliliter of a 0.5 percent solution of Evans blue dye and 8milligrams of egg albumin is injected intraveneously. After fortyminutes, the animal is sacrificed and the bleb size on its back ismeasured. The mean bleb size for the animals administered the testcompound is calculated and the percent inhibition is determined bycomparison with the control animal. A representative number of thecompounds were tested at dosage levels considerably below 200 milligramsper kilogram host body weight to establish the activity of the compoundsat minimal concentrations as low as 3 milligrams per kilogram host bodyweight.

Although the mechanism by which the compounds of this invention functionis not absolutely known, applicants have found that the compounds ofthis invention, in a manner believed to be similar to the function ofINTAL®, block reaction(s) in the mast cell leading to the production andrelease of mediators.

The compounds of this invention permit the occurrence of anon-productive antigen-antibody interaction. They effectively block theIgE type reaction and have little or no effect on the otherimmunoglobulins such as IgG, IgM, IgA and IgD.

The compounds of this invention have no pharmacological response patternsimilar to known anti-allergics in that they have no anti-hypertensiveactivity (no cardiovascular effect, etc.), they have no analgesicactivity, they have no central nervous system activity, they have noimmunosuppressive activity, they have no activity against histamine,serotonin, Bradykinin, etc. and they have no endocrinological activity.

In sum, the compounds of this invention block the release of mediatorscommonly resulting from the antigen-antibody reaction as exemplified ina passive cutaneous anaphylaxis test (PCA) using rat homocytotropicantibody -- a known correlate of human reaginic antibody.

By analogy to disodium cromoglycate and its activity correlation betweenstandard test animals, domestic animals and man, the compounds of thisinvention have been established as anti-allergic agents suitable for thesame uses at analogous doses and through the same routes ofadministration as INTAL®. Several of the compounds of this inventionhave been found to be effective anti-allergic agents when administeredorally. The orally active compounds of special interest are the loweralkyl pyridyloxamates their N-oxides, lower alkyl and cyano ringsubstituted derivatives (methyl, ethyl and propyl 2-pyridyloxamates,ethyl 4-pyridyloxamate, ethyl 5-pyridyl-oxamate), N-(2-pridyl)oxamicacid N'-oxide ethyl ester, (6-methyl-2-pyridyl)oxamic acid ethyl ester,(3-cyano-2-pyridyl)oxamic acid ethyl ester, the lower alkylpyrazinyloxamates (ethyl 2-pyrazinyloxamate), methyl, ethyl and i-propyloxanilate, 1H-tetrazole-5-carboxanilide, ethyl 3'-methyloxanilate, ethyl4'-methoxyoxanilate, ethyl and secondary butyl2'-carbamoyl-3'-methoxyoxanilate, ethyl4'-nitro-3'-(trifluoromethyl)oxanilate and ethyl 1-naphthyloxamate,2'-carbamoyl-3'-(2-hydroxypropoxy)oxanilic acid ethyl ester,(2-carbamoyl-3, 5-dimethoxyphenyl)oxamic acid ethyl ester, oxlic acid(2-[2-aminocarbonyl-3-ethoxy carbonylcarbonylaminophenoxy]ethyl)ethylester, [2-carbamoyl-3(2-hydroxyethoxy)phenyl]oxamic acid ethyl ester,3-benzyloxy-2-carbamoylphenyl)oxamic acid ethyl ester,(4-dimethylaminophenyl)oxamic acid ethyl ester,(2-(aminocarbonyl)-3-(dimethylamino)phenyl]oxamic acid ethyl ester,[2-carbamoyl-3-(methylthio)phenyl]oxamic acid ethyl ester and[(2-aminocarbonyl-3-methylsulfinylphenyl)amino]oxo acetic acid ethylester.

Thus, there is provided herewith a method for suppressing allergicmanifestations of atopic immediate sensitivity in warm-blooded human andnon-human animals, the latter including domesticated animals such as themouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse, cow, and thelike, by administering an effective amount of one or more of thecompounds disclosed in this application by oral, topical,intraperitoneal, intramuscular or intravenous routes. Since thecompounds of this invention afford no pharmacological response patternsimilar to or antagonistic to common anti-allergics, they may beadministered in conjunction with known compounds effectinganti-histamic, anti-hypertensive, analgesic, central nervous systemdepressant, immunosuppressive, anti-serotonin, anti-Bradykinin orendocrinological responses. In addition, those conventional adjuvantsknown to the art may be combined with the anti-allergics of thisinvention to provide compositions and solutions for administrativepurposes, although it is considered desirable and feasible to employ theanti-allergics as neat or pure compounds without additives other thanfor purposes of providing suitable pharmaceutical solution or liquid orvapor suspensions.

The effective dose range in test animals has been established to be fromabout 1.5 milligrams per kilogram to a dosage resulting in 100 percentprevention of allergic responses at 5 milligrams per kilogram host bodyweight upon administration intraperitoneally. The oral dose range liesfrom about 1.5 milligrams per kilogram to 90 percent prevention ofallergic response at 200 milligrams per kilogram host body weight. As aninhalant the dose is from that of INTAL®, (about 2 milligrams) to 1/20ththat quantity administered as needed prior to attack. Thus the dosagecontemplated for human use based upon the potency of the compoundsadministered lies from about 100 milligrams to 1 gram, preferably 250milligrams to about 750 milligrams in unit dosage form to beadministered when necessary and to the degree of the desired response,in single or plural doses under the guidance of a physician.

The compounds of this invention have not been found to be toxic to mice,the standard experimental animal in toxicity studies of this nature, atany administered dose up to and in excess of two grams per kilogram hostbody weight. No toxic level has been found in other standard testanimals. the anti-allergic compounds of this invention appear to be freefrom side effects common to other anti-allergics such as sedation,dizziness, depression, etc.

The aromatic and heterocyclic oxamic acid derivatives are generallyprepared by reaction of an appropriately substituted aromatic amine orheterocyclic amine with an appropriately substituted oxalylchloride inthe presence of an acid acceptor, such as pyridine, at ambienttemperature. The technique employed in the preparation of each of thespecially disclosed compounds is presented in the following workingexamples either in detail or by citation of the appropriate literature,the latter being incorporated herein by reference. Throughout thefollowing Examples, reference is made to CA (Chemical Abstracts), Zh.Obshch. Khim (The Journal of General Chemistry - Russia), Rec. Trav.Chim (Recueil des Travaux Chimique des Pays-Bas-Netherlands), Heilbron(Dictionary of Organic Compounds), Ber. Deut. Chem. (Berichte derdeutschen chemischen Gesellschaft), J. Org. Chem. (Journal of OrganicChemistry), J.A.C.S. (Journal of the American Chemical Society) andFarmaco, Ed. Sci. (Il Farmaco Scientifica Edition - Italy).

In the working examples, the number following the entitled compoundrefers to intraperitoneal/oral activity data obtained at a dosage levelof 200 milligrams per kilogram host body weight, unless otherwiseindicated. The activity data represents the percent inhibition of themean bleb size of sensitized rats administered the named compound inaccordance with the test procedure presented, supra. The oral data isrepresentatively presented for those compounds exhibiting inhibition offifty percent or more of the weal size in the test animals at 200milligrams per kilogram host body weight unless otherwise indicated.

EXAMPLE 1 (2-Thiazolyl)oxamic acid etyl ester. 100

The title compound is known in the literature: C.A.: 60 (10591c). Zh.Obshch Khim., 34(1), 28-32 1964). It is crystallized from ethanol, m.p.174°-177° C.

EXAMPLE 2 (2-Pyridyl)oxamic acid ethyl ester. 100/95

The title compound is known in the literature: P.A. Petyunin et.al., Zh.Obshch. Khim., 32, 1395- 8 (1962). It is crystallized from diethylether, m.p. 73°-75° C.

EXAMPLE 3 (2-Pyrimidyl)oxamic acid ethyl ester. 82

2-Aminopyrimidine (2.85 g, 0.03 mole) is condensed with 3.7 ml. (0.033mole) of ethyl oxalyl chloride in 100 ml. dichloromethane in thepresence of 4.83 ml. (0.06 mole) pyridine at 10° C. with stirring,giving 2.06 g. of the title compound, m.p. 96°-99° C., aftercrystallization from ethanol.

Elemental Analysis for C₈ H₉ N₃ O₃ : Calc'd: C, 49.23; H, 4.65; N,21.53. Found: C, 49.05; H, 4.68; N, 21.57.

EXAMPLE 4 (4-Pyridyl)oxamic acid ethyl ester. 100/34

4-Aminopyridine (2.82 g, 0.03 mole) is condensed with 3.7 ml. (0.033mole) of ethyl oxalyl chloride in a manner similar to example 3, giving1.26 g of the title compound, m.p. 110°-113° C., after crystallizationfrom diethyl ether.

Elemental Analysis for C₉ H₁₀ N₂ O₃ : Calc'd: C, 55.66; H, 5.19; N,14.43. Found: C, 55.88; H, 5.15; N, 14.64.

EXAMPLE 5 (3-Pyridyl)oxamic acid ethyl ester. 100/84

3-Aminopyridine (2.82 g., 0.03 mole) is condensed with 3.7 ml. (0.033mole) of ethyl oxalyl chloride in a manner similar to example 3, giving2.36 g of the title compound, m.p. 98°-100° C., after crystallizationfrom diethyl ether.

Elemental Analysis for C₉ H₁₀ N₂ O₃ : Calc'd: C, 55.66; H, 5.19; N,14.43. Found: C, 55.40; H, 5.13; N, 14.71.

EXAMPLE 6 (2-Pyrazinyl)oxamic acid ethyl ester. 100/83

Aminopyrazine (2.88 g., 0.03 mole) is condensed with 3.7 ml. (0.033mole) of ethyl oxalyl chloride in a manner similar to example 3, giving3.63 g. of the title compound, m.p. 134°-137° C., after crystallizationfrom ethanol.

Elemental analysis for C₈ H₉ N₃ O₃ : Calc'd: C, 49.23; H, 4.65; N,21.53. Found: C, 48.99; H, 4.58; N, 21.56.

EXAMAPLE 7 (2-Pyridyl)oxamic acid methyl ester. 77/100

2-Aminopyridine (2.82 g, 0.03 mole) is condensed with 3.04 ml. (0.033mole) of methyl oxalyl chloride in a manner similar to example 3, giving3.18 g of the title compound, m.p. 102°-106° C., after crystallizationfrom diethyl ether.

Elemental Analysis for C₈ H₈ N₂ O₃ : Calc'd: C, 53.33; H, 4.48; N,15.55. Found: C, 53.54; H, 4.47; N, 15.76.

EXAMPLE 8 (2-Pyridyl)oxamic acid n-propyl ester. 58/77

2-Aminopyridine (2.82 g, 0.03 mole) is condensed with 4.26 ml (0.033mole) of n-propyl oxalyl chloride in a manner similar to example 3,giving 2.2 g of the title compound, m.p. 56°-59° C., aftercrystallization from diethyl ether.

Elemental Analysis for C₁₀ H₁₂ N₂ O₃ : Calc'd: C, 57.68; H, 5.81; N,13.36. Found: C, 57.72; H, 5.84; N, 13.48.

EXAMPLE 9 (2-Pyridyl)oxamic acid isopropyl ester. 100

2-Aminopyridine is condensed with isopropyl oxalyl chloride in a mannersimilar to example 3 to afford the title compound as a liquid.

Elemental Analysis for C₁₀ H₁₂ N₂ O₃ : Calc'd: C, 57.68; H, 5.81; N,13.46. Found: C, 57.15; H, 6.04; N, 13.51.

EXAMPLE 10 (2-Pyridyl)oxamic acid n-butyl ester. 100

2-Aminopyridine is condensed with n-butyl oxalyl chloride in a mannersimilar to example 3 to afford the title compound, m.p. 35°-37° C.

Elemental Analysis for C₁₁ H₁₄ N₂ O₃ : Calc'd: C, 59.45; H, 6.35; N,12.60. Found: C, 59.16; H, 6.72; N, 12.45.

EXAMPLE 11 (2-Pyridyl)oxamic acid cyclohexyl ester. 53

2-Aminopyridine is condensed with cyclohexyl oxalyl chloride in a mannersimilar to example 3 to afford the title compound, m.p. 62°-64° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₃ : Calc'd: C, 62.89; H, 6.50; N,11.28. Found: C, 63.22; H, 7.00; N, 11.08.

EXAMPLE 12 (2-Pyridyl)oxamic acid sec-butyl ester. 100

2-Aminopyridine is condensed with secondary butyl oxalyl chloride in amanner similar to the procedure of example 3 to afford the titlecompound as a liquid, b.p. 112°-116° C./0.05 mm Hg.

Elemental Analysis for C₁₁ H₁₄ N₂ O₃ : Calc'd: C, 59.45; H, 6.35; N,12.60. Found: C, 59.48; H, 6.62; N, 12.60.

EXAMPLE 13 Oxanilic acid ethyl ester. 100/64

The title compound is known in the literature: G. Tiere, Rec. Trav.Chim., 52, 420- 4 (1933). It is crystallized from ethanol, m.p. 64°-67°C.

EXAMPLE 14 Oxanilic acid methyl ester. 100/52

The title compound is known in the literature: Heilbron Dict. of Org.Cpds., IV, p. 32. (1965). It is crystallized from diethyl ether, m.p.113°-116° C.

EXAMPLE 15 Oxanilic acid n-propyl ester. 82

The title compound is known in the literature: Heilbron Dict. of Org.Cpds., Vol. IV, p. 32, (1965). It is crystallized from diethyl ether,m.p. 90°-92° C.

EXAMPLE 16 Oxanilic acid i-propyl ester. 100/60

The title compound is known in the literature: Heilbron Dict. of Org.Cpds., Vol. IV, p. 32 (1965). It is crystallized from pentane, m.p.51°-53° C.

EXAMPLE 17 Oxanilic acid phenyl ester. 59

The title compound is known in the literature; R. Stolle et. al., Ber.Deut. Chem., 54B, 1312-20 (1921). It is crystallized from ethanol, m.p.136°-139° C.

EXAMPLE 18 1H-Tetrazole-5-carboxanilide. 100/100

The title compound is known in the literature: B. E. Fisher, et. al., J.Org. Chem., 24, 1650 (1959). It is crystallized from ethanol-water, m.p.216°-218° C. (dec.).

EXAMPLE 19 2'-Carboxyoxanilic acid 1-ethyl ester. 50

The title compound is known in the literature: J.A.C.S. 32, 119 (1910).It is crystallized from toluene, m.p,. 182°-183° C.

EXAMPLE 20 2'-Carbamoyloxanilic acid ethyl ester. 90

The title compound is known in the literature: B. R. Baker et. al., J.Org. Chem., 27, 4672 (1962). It is crystallized from ethanol, m.p.160°-161° C.

EXAMPLE 21 2'-Cyanooxanilic acid ethyl ester. 53

2'-Carbamoyloxanilic acid ethyl ester (5 g, 0.021 mole) is refluxed in50 ml of acetic anhydride for 2 hrs. The solvent is removed on a rotaryevaporator and the residue is slurried in water and diethyl ether,separated, and the ether layer is washed with sat. NaHCO₃, brine anddried with Na₂ SO₄. Evaporation of the ether gives 5 g of a residuewhich is chromatographed on 150 g silica gel with benzene. Elution with10 percent diethyl ether in benzene removes 0.68 g of the titlecompound, m.p. 90°-91° C. after crystallization from ethanol.

Elemental Analysis for C₁₁ H₁₀ N₂ O₃ : Calc'd: C, 60.54; H, 4.62; N,12.84. Found: C, 60.36; H, 4.50; N, 12.67.

EXAMPLE 22 2'-Methyloxanilic acid ethyl ester. 75

The title compound is known in the literature: P. E. Todesco et. al.,C.A. 61:419f. It is a liquid, b.p. 126° C./0.05 mm. Hg.

EXAMPLE 23 2'-Methoxyoxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A.:61 (4192). It iscrystallized from benzene, m.p. 81°-85° C.

EXAMPLE 24 3'-Methoxyoxanilic acid ethyl ester. 38

The title compound is known in the literature: P. A. Petyunin et. al.,Zh. Obshch. Kim., 21, 1859-61 (1951). It is crystallized frommethanol-water, m.p. 95°-98° C.

EXAMPLE 25 3'Trifluoromethyloxanilic acid ethyl ester. 64

The title compound is known in the literature: A. Buruffini, et. al.,Farmaco, Ed. Sci., 22 (9), 717-34 (1967). It is crystallized fromethanol, m.p. 120°-123° C.

EXAMPLE 26 3'-Fluorooxanilic acid ethyl ester. 78

m-Fluoroaniline (5.55 g, 0.05 mole) is condensed with 6.16 ml (0.055mole) of ethyl oxalyl chloride in a manner similar to example 3, giving9.26 g of the title compound, m.p. 85°-89° C. after crystallization fromethanol.

Elemental Analysis for C₁₀ H₁₀ FNO₃ : Calc'd: C, 57.0; H, 4.78; N, 6.64.Found: C, 56.45; H, 4.87; N, 6.61.

EXAMPLE 27 3'-Methyloxanilic acid ethyl ester. 85

The title compound is known in the literature: P. A. Petyunin et. al.,Zh, Obshch. Khim., 24, 1078-82 (1954). It is crystallized frombenzene-hexane, m.p. 56°-60° C.

EXAMPLE 28 4'-Carbamoyloxanilic acid ethyl ester. 55

p-Aminobenzamide (4.08 g. 0.03 mole) is condensed with 3.7 ml (0.033mole) of ethyl oxalyl chloride in a manner similar to example 3, giving2.85 g of the title compound, m.p, 259°-264° C. (dec.), aftercrystallization from N,N-dimethylformamide.

Elemental Analysis for C₁₁ H₁₂ N₂ O₄ : Calc'd: C, 55.93; H, 5.12; N,11.86. Found: C, 56.01; H, 5.24; N, 11.92.

EXAMPLE 29 4'-Methoxyoxanilic acid ethyl ester. 75/76

The title compound is known in the literature: A. Piutti et. al., Br.Deut. Chem., 31, 330-336 (1898). It is crystallized from ethanol, m.p.100°-104° C.

EXAMPLE 30 4'-Nitrooxanilic acid ethyl ester. 75

The title compound is known in the literature: G. Tierie, Rec. Trav.Chim., 52, 420-4 (1933). It is crystallized from acetic acid, m.p.169°-172° C.

Example 31 4'-Methyloxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A. 61 (4192g). It iscrystallized from benzene-hexane, m.p. 65°-67° C.

EXAMPLE 32 4'-Phenylazooxanilic acid ethyl ester. 41

p-Phenylazoaniline (5.92 g, 0.03 mole) is condensed with 3.7 ml (0.033mole) of ethyl oxalyl chloride in a manner similar to example 3, giving7.36 g of the title compound, m.p. 157°-160° C., after crystallizationfrom ethanol.

Elemental Analysis for C₁₆ H₁₅ N₃ O₃ : Calc'd: C, 64.63; H, 5.09; N,14.14. Found: C, 64.61; H, 5.13; N, 14.04.

EXAMPLE 33 -Phenylenebisoxamic acid diethyl ester. 77

The title compound is known in the literature: C.A. 60 (P3012b). It iscrystallized from ethanol, m.p. 214°-217° C.

EXAMPLE 34 2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 100/94

6-Amino-o-anisamide (8.75 g, 0.0527 mole) is condensed with 6.2 ml(0.0554 mole) of ethyl oxalyl chloride in a manner similar to example 3,giving 8.35 g of the title compound, m.p. 170°-173° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calc'd: C, 54.13; H, 5.30; N,10.52. Found: C, 54.36; H, 5.20; N, 10.66.

EXAMPLE 35 2-Carboxy-3'-methoxyoxanilic acid ethyl ester. 54

6-Amino-o-anisic acid (1.671 g, 0.01 mole) is condensed with 1.23 ml(0.011 mole) of ethyl oxalyl chloride in a manner similar to example 3,giving 1 g of the title compound, m.p. 142°-144° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₂ H₁₃ NO₆ : Calc'd: C, 53.93; H, 4.90; N, 5.24Found: C, 54.21; H, 4.99; N, 5.32.

EXAMPLE 36 2'-Cyano-3'-methoxyoxanilic acid ethyl ester. 80/71

2-Amino-6-methoxybenzonitrile (4.67 g, 0.0315 mole) is condensed with3.88 ml (0.0346 mole) of ethyl oxalylchloride in a manner similar toexample 3, giving 5.0 g of the title compound, m.p. 142°-145° C., aftercrystallization from toluene.

Elemental Analysis for C₁₂ H₁₂ N₂ O₄ : Calc'd: C, 58.06; H, 4.87; N,11.29. Found: C, 58.21; H, 4.93; N, 11.02.

EXAMPLE 37 2'-Carbamoyl-3'-chlorooxanilic acid ethyl ester. 25

2-Amino-6-chlorobenzamide (4.26 g, 0.025 mole) is condensed with 3.1 ml(0.0275 mole) of ethyl oxalyl chloride in a manner similar to example 3,giving 5.28 g of the title compound, m.p. 190°-193° C., aftercrystallization from ethanol.

Elemental analysis for C₁₁ H₁₁ CIN₂ O₄ : Calc'd: C, 48.8; H, 4.10; N,10.35. Found: C, 49.08; H, 4.05; N, 10.72,

EXAMPLE 38 2'-Carboxy-3'-methoxyoxanilic acid 1-ethyl 2'-methyl ester.78

Methyl 6-methoxyanthranilic acid (3.62 g, 0.02 mole) is condensed with2.46 ml (0.022 mole) of ethyl oxalyl chloride in a manner similar toexample 3, giving 3.51 g of the title compound, m.p. 96°-99° C. aftercrystallization from ethanol.

Elemental Analysis for C₁₃ H₁₅ NO₆ : Calc'd: C, 55.51; H, 5.38; N, 4.98.Found: C, 55.56; H, 5.43; N, 5.18.

EXAMPLE 39 2'-Carbamoyl-3'-(2-phenoxyethoxy)oxanilic acid ethyl ester.75

2-Phenoxyethanol (4.15 ml, 0.033 mole) is added to dimethylsulfoxylsodium prepared from 1.39 g. of 57 percent sodium hydride and 40 mldimethylsulfoxide, giving a mixture of the solid salt of the alcoholafter about 20 minutes. This mixture is added to a solution of 5.8 g(0.030 mole) 2,6-dinitrobenzonitrile in 20 ml of dimethylsulfoxide at30°-40° C., and the resulting purple solution is stirred over night atroom temperature. The solvent is removed at 70° C. on a rotaryevaporator, and the residue is triturated with water. A solid isfiltered off and it is dissolved in ethylacetate. The ethylacetatesolution is washed twice with H₂ O, brine, and dried with calciumsulfate. Evaporation of the ethylacetate, gives 8.5 g of2-nitro-6(2-phenoxyethoxy)benzonitrile, which is crystallized from 200ml ethyl alcohol, giving 6 g, m.p. 129°-137.5° C.

The crystallized 2-nitro-6-(2-phenoxyethoxy)benzonitrile (5.82 g, 0.0205mole) is stirred in 116 ml absolute ethanol at 50° C. and 3.62 ml.(0.0615 mole) 85 percent hydrazine hydrate is added, followed by smallscoops of Raney nickel. The temperature is kept at 50°-60° C. while theRaney nickel is added, and after gas evolution and the exotherm ceases,the mixture is filtered through diatomaceous earth. The filter cake iswashed with hot ethanol and the filtrate is concentrated, giving 2.804 gof 2-amino-6-(2-phenoxyethoxy)benzamide m.p. 127°-130° C.

Elemental Analysis for C₁₅ H₁₆ N₂ O₃ : Calc'd: C, 66.16; H, 5.92; N,10.29. Found: C, 66.71; H, 6.36; N, 10.13.

2-Amino-6-(2-phenoxyethoxy)benzamide (2.8 g, 0.0103 mole) is condensedwith 1.26 ml (0.0113 mole) of ethyl oxalyl chloride in a manner similarto example 2, giving 1.62 g of the title compound, m.p. 142°-145° C.,after crystallization from ethanol.

Elemental Analysis for C₁₉ H₂₀ N₂ O₆ : Calc'd: C, 61.28; H, 5.41; N,7.52. Found: C, 61.14; H, 5.57; N, 7.50.

EXAMPLE 40 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 96

6-Amino-o-anisamide (4.98 g, 0.03 mole) is condensed with 3.04 ml.(0.033 mole) of methyl oxalyl chloride in a manner similar to example 3,giving 4.24 g of the title compound, m.p. 195°-198° C., aftercrystallization from methanol.

Elemental Analysis for C₁₁ H₁₂ N₂ O₅ : Calc'd: C, 52.38; H, 4.80; N,11.11. Found: C, 52.30; H, 4.94; H, 11.40.

EXAMPLE 41 2'-Carbamoyl-3'-methoxyoxanilic acid n-propyl ester. 96

6-Amino-o-anisamide (4.98 g, 0.03 mole) is condensed with 4.25 ml (0.033mole) of n-propyl oxalyl chloride in a manner similar to example 3,giving 4.81 g of the title compound, m.p. 158°-161° C., aftercrystallization from acetonitrile.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calc'd: C, 55.71; H, 5.75; N,10.00. Found: C, 55.92; H, 5.93; N, 10.34.

EXAMPLE 42 2'-Carbamoyl-3'-methoxyoxanilic acid isopropyl ester. 57

6-Amino-o-anisamide (4.98 g, 0.03 mole) is condensed with 4.25 ml (0.033mole) of isopropyl oxalyl chloride in a manner similar to example 3,giving 4.74 g of the title compound m.p. 128°-132° C., aftercrystallization from benzene.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calc'd: C, 55.71; H, 5.75; N,10.00. Found: C, 55.66; H, 5.93N, 10.38.

EXAMPLE 43 2'-Carbamoyl-3'-methoxyoxanilic acid. 48

2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (1.33 g, 0.005 mole) isstirred in 50 ml water, and 5.0 ml of N NaOh is slowly added, giving asolution. After 1/2 hour the solution is filtered, and the filtrate isacidified to pH 2 with N HCl, giving 0.71 g of the title compound, m.p.214°-215° C., after crystallization from ethanol.

Elemental Analysis for C₁₀ H₁₀ O₅ N₂ : Calc'd: C, 50.42: H, 4.23; N,11.76. Found: C, 50.60; H, 4.35; N, 11.80.

EXAMPLE 44 N-(2-Carbamoyl-3-methoxyphenyl)oxamide. 26

2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (5.0 g, 0.0188 mole) isadded to 50 ml of ethanol saturated with ammonia at 0°-5° C., and themixture is stirred in an ice-bath for 2 hours, then filtered. The cakeis washed with ethanol, giving 1.41 g of the title compound, m.p.252°-255° C., after crystallization from water.

Elemental Analysis for C₁₀ H₁₁ N₃ O₄ : Calc'd: C, 50.63; H, 4.67; N,17.72. Found: C, 50.45; H, 4.70; N, 17.65.

EXAMPLE 45 2'-Carboxy-4'-methoxyoxanilic acid ethyl ester. 61

5-methoxyanthranilic acid (1.67 g, 0.01 mole) is condensed with 1.23 ml(0.011 mole) of ethyl oxalyl chloride in a manner similar to example 3,giving 1.32 g of the title compound, m.p. 238°-243° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₂ H₁₃ NO₆ : Calc'd: C, 53.93; H, 4.90; N, 5.24.Found: C, 53.99; H, 4.93; N, 4.99.

EXAMPLE 46 2'-Carbamoyl-4'-chlorooxanilic acid ethyl ester. 58

2-Amino-5-chlorobenzamide (3.41 g, 0.02 mole) is condensed with 2.46 ml(0.022 mole) of ethyl oxalyl chloride in a manner similar to example 3,giving 4.57 g of the title compound, m.p. 204°-210° C., aftercrystallization from acetonitrile.

Elemental Analysis for C₁₁ H₁₁ ClN₂ O₄ : Calc'd: C, 48.8; H, 4.10; N,10.35; Cl, 13.10. Found: C, 48.65; H, 3.98; N, 10.26; Cl, 12.84.

EXAMPLE 47 2'-Carbamoyl-4'-nitrooxanilic acid ethyl ester. 59

2-Amino-5-nitrobenzamide (5.43 g, 0.03 mole) is condensed with 3.7 ml(0.033 mole) of ethyl oxalyl chloride in a manner similar to example 3,giving 6.54 g of the title compound, m.p. 206°-209° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₁ H₁₁ N₃ O₆ : Calc'd: C, 46.98; H, 3.94; N,14.94. Found: C, 46.68; H, 3.96; N, 15.12.

EXAMPLE 48 4'-Methoxy-2'-nitrooxanilic acid ethyl ester. 84

The title compound is known in the literature: Zh. Obshch. Khim. 1,2471-7 (1937). It is crystallized from ethanol, m.p. 154°-160° C.

EXAMPLE 49 2'-Nitro-4'-(trifluoromethyl)oxanilic acid ethyl ester. 29

4-Amino-4-nitrobenzotrifluoride (3.21 g, 0.03 mole) is condensed with3.7 ml (0.033 mole) of ethyl oxalyl chloride in a manner similar toexample 3, giving 7.01 g of the title compound, m.p. 124°-126° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₁ H₉ F₃ N₂ O₅ : Calc'd: C, 43.1; H, 2.96; N,9.16. Found: C, 42.97; H, 3.02; N, 9.28.

EXAMPLE 50 2'-Carbamoyl-5'-methoxyoxanilic acid ethyl ester. 91

2-Nitro-4-methoxybenzonitrile (12.8 g) is reduced in a manner similar toexample 40, giving 9.0 g of 2-amino-p-anisamide, m.p. 152°-156° C.,after crystallization from water.

Elemental Analysis for C₈ H₁₀ N₂ O₂ : Calc'd: C, 57.82; H, 6.07; N,16.86. Found: C, 58.60; H, 5.76; N, 16.65.

2-Amino-p-anisamide (4.99 g, 0.03 mole) is condensed with 3.68 ml (0.033mole) of ethyl oxalyl chloride in a manner similar to example 3, giving3.84 g of the title compound, m.p. 186°-188° C., after crystallizationfrom ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calc'd: C, 54.13; H, 5.34; N,10.52. Found: C, 54.29; H, 5.50; N, 10.89.

EXAMPLE 51 5'-Chloro-2'-sulfamoyloxanilic acid ethyl ester. 70

2-Amino-4-chlorobenzenesulfonamide (4.13 g, 0.02 mole) is condensed with2.46 ml (0.022 mole) of ethyl oxalyl chloride in a manner similar toexample 3, giving 3.04 g of the title compound, m.p. 183°-187° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₀ H₁₁ CIN₂ O₅ S: Calc'd: C, 39.2; H, 3.65; N,9;14; S, 10.45. Found: C, 38.95; H, 3.65; N, 9.14; S, 10.86.

EXAMPLE 52

2'-Carboxy-4'-methoxyoxanilic acid 1-ethyl 2'-methyl ester. 58

6-Amino-m-anisic acid methyl ester (4.7 g, 0.0283 mole) is condensedwith 3.48 ml (0.0311 mole) of ethyl oxalyl chloride in a manner similarto example 3, giving 5.27 g of the title compound, m.p. 129°-133° C.,after crystallization from ethanol.

Elemental Analysis for C₁₃ H₁₅ NO₆ : Calc'd: C, 55.51; H, 5.38; N, 4.98.Found: C, 55.72; H, 5.38; N, 5.37.

EXAMPLE 53 2',6'-Dichlorooxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A.: 60 (1621a). It iscrystallized from diethyl ether, m.p. 128°-130° C.

EXAMPLE 54

4'-Nitro-3'-(trifluoromethyl)oxanilic acid ethyl ester. 100/73

5-Amino-2-nitrobenzotrifluoride (6.18 g, 0.03 mole) is condensed with3.7 ml (0.033 mole) of ethyl oxalyl chloride in a manner similar toexample 3, giving 6.07 g of the title compound, m.p. 106°-110° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₁ H₉ F₃ N₂ O₅ : Calc'd: C, 43.1; H, 2.96; N,9.16. Found: C, 43.26; H, 2.95; N, 9.18.

EXAMPLE 55 4,4'-Oxydioxanilic acid diethyl ester. 34

The title compound is known in the literature: CA.: 60 (P 3012b). It iscrystallized from ethanol, m.p. 159°-162° C.

EXAMPLE 56 2' -Carbamoyl-3'-methoxyoxanilic acid cyclohexyl ester. 91

6-Amino-o-anisamide is condensed with cyclohexyl oxalyl chloride toafford the title compound, m.p. 166°-169° C.

Elemental Analysis: C₁₆ H₂₀ N₂ O₅ : Calc'd: C, 59.99; H, 6.29; N, 8.75.Found: C, 60.17; H, 6.33; N, 8.69.

EXAMPLE 57 2'-Carbamoyl-3'-methoxyoxanilic acid butyl ester. 98

6-Amino-o-anisamide is condensed with n-butyl oxalyl chloride to affordthe title compound, m.p. 126°-129° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₅ : Calc'd: C, 57.13; H, 6.11; N,9.52. Found: C, 57.43; H, 6.46; N, 9.38.

EXAMPLE 58 2'-Carbamoyl-3'-methoxyoxanilic acid sec-butyl ester. 100/70

6-Amino-o-anisamide is condensed with secondary butyl oxalyl chloride toafford the title compound, m.p. 119°-122° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₅ : Calc'd: C, 57.13; H, 6.17; N,9.52. Found: C, 56.94; H, 6.44; N, 9.50.

EXAMPLE 59

2' -Carbamoyl-3'-ethoxyoxanilic acid ethyl ester. 80

2-Amino-6-ethoxy-benzoic acid amide is condensed with ethyl oxalylchloride to afford the title compound m.p. 142°-145° C.

EXAMPLE 60 2'-Carbamoyl-3'-propoxyoxanilic acid ethyl ester. 52

2-Amino-6-propoxy-benzoic acid amide is condensed with ethyl oxalylchloride to afford the title compound, m.p. 130°-133° C.

EXAMPLE 61 2'-Carbamoyl-3'-isopropoxyoxanilic acid ethyl ester. 60

2-Amino-6-isopropoxy-benzoic acid amide is condensed with ethyloxalylchloride to afford the title compound, m.p. 123°-125° C.

EXAMPLE 62 2'-Carbamoyl-3'-n-butoxyoxanilic acid ethyl ester. 75

2-Amino-6-n-butoxy-benzoic acid amide is condensed with ethyl oxalylchloride to afford the title compound, m.p. 120°-123° C.

EXAMPLE 63 (2-Naphthyl)oxamic acid ethyl ester. 76

The title compound is known in the literature: C.A. 43:697 g, m.p.118°-120° C.

EXAMPLE 64 (1-Naphthyl)oxamic acid ethyl ester. 97

The title compound is known in the literature: C.A. 43:6973 g, m.p.105°-107° C.

EXAMPLE 65 3', 4', 5'-Trimethoxyoxanilic acid ethyl ester. 63

The title compound is known in the literature: C.A. 68:9547 y, m.p.132°-134° C.

Elemental Analysis for C₁₃ H₁₇ NO₆ : Calculated: C, 55.12; H, 6.05; N,4.95. Found: C, 55.14; H, 6.26; N, 4.87.

EXAMPLE 66 N-(2-Pyridyl)oxamic acid N'-oxide ethyl ester. 94/51

A solution of 4.07 g. (0.02 mole) of 85% m-chloroperbenzoic acid in 75ml. of CHCl₃ was dropped into a solution of 3.88 g. (0.02 mole) ofN-(2-pyridyl) oxamic acid ethyl ester in 50 ml. of CHCl₃. After stirringovernight at room temperature, the solution was passed through a columnof Grade I Woelm basic alumina followed by 400 ml. of CHCl₃. Elutionwith 800 ml. of 3:1 CHCl₃ /CH₃ OH gave 1.31 g. after crystallizationfrom ethylacetatehexane: mp. 128°-130° C.

Elemental Analysis for C₉ H₁₀ N₂ O₄ : Calc'd: C, 50.76; H, 4.67; N,13.45; Found: C, 51.00; H, 4.67; N, 13.58.

EXAMPLE 67 3' -Methoxy-2'-methylcarbamoyloxanilic acid ethyl ester. 72

Slow addition of 4.98 g. (0.03 mole) of 6-amino-o-anisamide to a mixtureof 57% NaH (1.32 g., 0.0315 mole) in 50 ml. dimethylformamide wascarried out at room temperature. After the evolution of H₂ ceased, themixture was cooled to 3° C. and 2.06 ml. (0.033 mole) of methyliodidewas slowly added at 3°-5° C. The temperature was allowed to go up toroom temperature and stir for 2 hours. The mixture was concentrated, theresidue extracted into ethylacetate-water, the mixture was basified, andthe ethylacetate layer was washed with water, brine and dried.Concentration gave a tan solid that was crystallized (ethanol), giving0.45 g. (8%) of 6-amino-N-methyl-o-anisamide mp. 186°-189° C.

Elemental Analysis for C₉ H₁₂ N₂ O₂ : Calc'd: C, 59.98; H, 6.71; N,15.55; Found: C, 00.42; H, 7.04; N, 15.42.

To a solution of 6-amino-N-methyl-o-anisamide ( 2.85 g., 0.0158 mole)and 2.54 ml. (0.0314 mole) of pyridine in 100 ml. of CH₂ Cl₂ at 10° C.,is added 1.94 ml. (0.0174 mole) of ethyl oxalyl chloride over 5 minutes.After stirring for 2 hours at room temperature, add diethyl ether andwash with water and cold dilute HCl. An insoluble solid is filtered offand crystallized from ethylacetate-hexane, giving 0.3 g. of the titlecompound (mp. 119°- 121° C.). The original organic layer is washed withwater, brine and dried with Na₂ SO₄. Concentration and crystallizationof the residue from ethyl acetate-hexane, gave 0.91 g. of the titlematerial: mp. 119°-121° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calc'd: C, 55.71; H, 5.75; N,10.00; Found: C, 55.91; H, 6.00; N, 9.94.

EXAMPLE 68 2'-Carbamoyl-3'-(2-dimethylaminoethoxy)oxanilic acid ethylester, hydrochloride. 85

Ethyl oxalyl chloride (0.91 ml., 0.008 mole) is added to 1.81 g. (0.008mole) of 2-amino-6-dimethylaminoethoxybenzamide at 10° C. in 100 ml. ofCH₂ Cl₂ over a period of 5 minutes. After stirring overnight, themixture is concentrated to dryness on a rotary evaporater and theresidue is triturated with diethyl ether and filtered. The solid iscrystallized from methanol, giving 1.89 g. of the title compound: mp.209°-211° C.

Elemental Analysis for C₁₅ H₂₂ ClN₃ O₅.0.15 H₂ O Calc'd: C, 49.70; H,6.2; N, 11.6; Cl, 9.78; Found: C, 49.92; H, 6.66; N, 11.64; Cl, 9.85.

The 2-amino-6-dimethylaminoethoxybenzamide reactant is prepared asfollows:

To a solution of 14.06 g. (0.0728 mole) of 2,6-dinitrobenzonitrile in270 ml. of tetrahydrofuran at 40° C., a solution prepared by adding 1.67g. (0.0726 mole) of sodium to 30 ml. of 2-dimethylaminoethanol is addedover 20 minutes. The solution is refluxed for 3 hours, concentrated todryness on a rotary evaporator and scrubbed three times with xylene. Theresidue is filtered with water, and crystallized from benzene-hexane,giving 7.79 g. of 2-(2-dimethylaminoethoxy)-6-nitrobenzonitrile mp.89°-91° C.

Elemental Analysis for C₁₁ H₁₃ N₃ O₃ : Calc'd: C, 56.16; H, 5.57; N,17.86; Found: C, 56.11; H, 5.70; N, 17.51.

To a solution of 7.17 g. (0.0305 mole) of2-(2-dimethylaminoethoxy)-6-nitrobenzonitrile and 3.85 ml. of 85%hydrazine hydrate in 250 ml. of absolute ethyl alcohol at 40° C. isadded small portions of Raney nickel. When the exotherm and evolution ofgases ceases, the mixture is filtered and the filtrate concentrated todryness. The residue is crystallized from ethyl acetatehexane, giving2.13 g. of 2-amino-6-dimethylaminoethoxybenzamide: m.p. 118°-121° C.

EXAMPLE 69 (6-Methyl-2-pyridyl)oxamic acid ethyl ester. 77/74

To a solution of 5.4 g. (0.05 mole) of 2-amino-6-picoline and 8.05 ml.(0.1 mole) of pyridine in 100 ml. of CH₂ Cl₂ at 10° C. is added 6.16 ml.(0.055 mole) of ethyl oxalyl chloride over 10 minutes. After stirringfor 2 hours at room temperature, the solution is concentrated to drynesson a rotary evaporator. The residue is triturated with water andfiltered. Crystallization (diethyl ether) gave 6.90 g.:mp. 61°-63° C.

Elemental Analysis for C₁₀ H₁₂ N₂ O₃ : Calc'd: C, 57.68; H, 5.81 N,13.46; Found: C, 58.19; H, 6.08; N, 13.28.

EXAMPLE 70 2-(Ethoxycarbonylcarboxamido)-4,5-dimethylbenzoic acid. 33

To a solution of 4,5-dimethylanthranilic acid (3.30 g., 0.02 mole) and3.22 ml. (0.04 mole) of pyridine in 50 ml. of tetrahydrofuran at 10° C.,is added 2.46 ml. (0.022 mole) of ethyl oxalyl chloride over 5 minutes.The reaction is carried out and worked up in a manner similar to example69, giving 4.27 g. of the title compound after crystallization(ethanol): mp. 235°-239° C.

Elemental Analysis for: C₁₃ H₁₅ NO₅ : Calc'd: C, 58.86; H, 5.70; N,5.28; Found: C, 59.15; H, 5.73; N, 5.20.

EXAMPLE 71 (2-Carbamoyl-4,5-dimethylphenyl)oxamic acid ethyl ester. 100

Liquid phosgene (55 g.) is added to a stirred solution of 30.1 g. (0.182mole) of 4,5-dimethylanthranilic acid in 800 ml. of dioxane. Thetemperature is raised to 40°-45° C. and held for 2 hours, and thenstirred overnight at room temperature. The mixture is filtered and thecake washed with diethyl ether, giving 33 g. of the isatoic anhydride:mp.>300° C. The isatoic anhydride is then added to 435 ml of N NNH₄ OH,and the mixture stirred overnight at room temperature. The mixture isrefluxed for 2 hours, cool, filter, and crystallize (ethanol), giving13.4 g. of 2-amino-4,5-dimethylbenzamide: mp.162°-7° C.

To a solution of 1.99 g. (0.0121 mole) of 2-amino-4,5-dimethylbenzamideand 1.95 ml. (0.0242 mole) of pyr dine in 50 ml. of tetrahydrofuran at10° C. is added 1.49 ml. (0.0133 mole) of ethyl oxalyl chloride over 5minutes. The reaction is carried out and worked-up in a manner similarto example 69, giving 2.73 g. of the title compound aftercrystallization (ethanol), mp. 190°-193 C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₄ : Calc'd: C, 59.08; H, 6.10; N,10.60. Found: C, 58.82; H, 6.31; N, 10.41.

EXAMPLE 72 2'-Acetyl-3'-methoxyoxanilic acid ethyl ester. 46

To a solution of 2-amino-6-methoxyacetophenone (2.1 g., 0.0127 mole) and2.05 ml. (0.0254 mole) of pyridine in 50 ml. of methylene chloride at10° C., is added 1.49 ml. (0.0133 mole) of ethyl oxalyl chloride over 5minutes. The reaction is carried out and worked-up in a manner similarto example 69, giving 2.06 g. of the title compound after chromatographyon acidic silica gel: mp. 70°-73° C.

Elemental Analysis for C₁₃ H₁₅ NO₅ : Calc'd: C, 58.86; H, 5.70; N, 5.28.Found: C, 58.89; H, 5.66; N, 5.23.

EXAMPLE 73 2'-Carbamoyl-3'-(2-hydroxypropoxy)oxanilic acid ethyl ester.100

In a manner similar to example 68, but using 1,2-propanediol instead of2-dimethylaminoethanol, one isolates a 39% yield of 2-(2-hydroxypropoxy)-6-nitrobenzonitrile after crystallization (benzene): mp.121°-124° C.

Elemental Analysis for C₁₀ H₁₀ N₂ O₄ : Calc'd: C, 54.05; H, 4.54; N,12.61. Found: C, 54.24; H, 4.64; N, 12.67.

2-Amino-6-(2-hydroxypropoxy)benzamide is produced by reducing thebenzonitrile in accordance with Example 68, in 78% yield aftercrystallization (ethylacetate-hexane): mp. 115°-118° C.

Elemental Analysis for C₁₀ H₁₄ N₂ O₃ : Calc'd: C, 57.13; H, 6.71, N,13.33. Found: C, 57.55; H, 6.56; N, 13.33.

To a solution of 2-amino-6-(2-hydroxy propoxy)benzamide (2.05 g.,0.00976 mole) and 1.57 ml. (0.01952 mole) of pyridine in 200 ml. of CH₂Cl₂ at 10° C., is added 1.09 ml. (0.00976 mole) of ethyl oxalyl chlorideover 20 minutes. The reaction is carried out and worked-up in a mannersimilar to example 69, giving 0.18 g. of the title material afterchromatography on acidic silica gel and crystallization (ethylacetate-hexane): mp. 131°-135° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₆ : Calc'd: C, 54.19; H, 5.85; H,9.03. Found: C, 54.38; H, 6.09; N, 8.97.

EXAMPLE 74 (2-Carbamoyl-3,5-dimethoxyphenyl)oxamic acid ethyl ester.100/19 at 25 mg/kg

A solution of 1.96 g. (0.01 mole) of 4,6-dimethoxy anthranilamide in 50ml. of methylenechloride is treated with pyridine and ethyl oxalylchloride. After 1 hour the reaction mixture is filtered and the crudeproduct is recrystallized from dimethylformamide-ethyl acetate to give2.4 g. of product, mp. 198°-208° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₆ : Calc'd: C, 52.70; H, 5.44; N,9.46; Found: C, 52.75; H, 5.56; N, 9.54.

4,6-Dimethoxyanthranilamide is prepared as follows:

A mixture of 6.7 g. (0.03 mole) of 4,6-dimethoxy isatoic anhydride and75 ml. of 1M ammonium hydroxide is stirred 16 hours at room temperature.The solid is filtered off, dried and extracted with hot ethanol. Theextracts are cooled and diethyl ether is added to give a first crop 1.2g., mp. 198°-200° C. followed by a second crop of the desired amide, mp.117°-119° C., 2.3 g.

Elemental Analysis for C₉ H₁₂ N₂ O₃ : Calc'd: C, 55.09; H, 6.17; N,14.28; Found: C, 55.01; H, 6.21; N, 14.12.

4,6-Dimethoxyisatoic anhydride is prepared from 4,6-dimethoxyanthranilicacid (H. Newman & R. Anzier, J. Org. Chem. 34, 3484 (1969)) and phosgeneaccording to the method of E. C. Wagner and M. F. Fegley, Org. Synthesis27, 45 (1947).

EXAMPLE 75 Oxalic acid (2-[2-aminocarbonyl-3-ethoxycarbonylcarbonylamino phenoxy]ethyl)ethyl ester. 82/26 at 10 mg/kg.

2-Amino-6-(2-hydroxyethoxy)benzamide is treated with two equivalents ofpyridine and ethyl oxalyl chloride. The usual workup gives a white solidwhich is triturated with hot ethanol and filtered to give the product,mp. 180°-182° C.

Elemental Analysis for C₁₇ H₂₀ N₂ O₉ : Calc'd: C, 51.51; H, 5.09; N,7.07; Found: C, 51.39; H, 5.00; N, 7.11.

2-Amino-6-(2-hydroxyethoxy)benzamide is prepared by the followingprocedure:

A suspension of 6.0 g. of 2-(2-hydroxyethoxy)-6-nitrobenzonitrile on 30ml. of ethanol and 4.3 ml. of hydrazine hydrate is added slowly to asuspension of 2.9 g. of Raney nickel in 50 ml. of ethanol at such a rateto keep the temperature at 65° C. The mixture is heated at reflux for1/2 hour after the addition is complete, filtered through Celite andevaporated to dryness. The solid is recrystallized from ethanol to give5.3 g. (94%) of amide, mp. 149°-151° C.

Elemental Analysis for C₉ H₁₂ N₂ O₃ Calc'd: C, 55.09; H, 6.17; N, 14.28;Found: C, 54.84; H, 6.17; N, 14.27.

The 2-(2-hydroxyethoxy)-6-nitrobenzonitrile is prepared as follows:

To a solution of 19.3 g. of 2,6-dinitrobenzonitrile in 500 ml. intetrahydrofuran at reflux is added dropwise a solution of lithiumhydroxyethoxide in tetrahydrofuran prepared by adding 62.5 ml. of 1.6 Mbutyllithium in hexane to a solution of 6.2 g. of ethylene glycol in 100ml. of tetrahydrofuran at -78° C. and stirring for 1 hour. After all theethoxide is added the reaction mixture is refluxed for 4 hours, cooledand evaporated to dryness. The resulting solid is extracted with hotbenzene which yields 8.5 g. of product on cooling, mp. 140°-142° C.

Elemental Analysis for C₉ H₈ N₂ O₄ : Calc'd: C, 51.92; H, 3.87; N,13.46; Found: C, 51.98; H, 3.92; N, 13.54.

EXAMPLE 76 [2-Carbamoyl-3-(2-hydroxyethoxy)phenyl]oxamic acid ethylester 12 at 10 mg/kg per os; 49 at 30 mg/kg per os; 43 at 100 mg/kg peros.

To a suspension of 5.8 g. (30 mmole) of2-amino-6-(2-hydroxyethoxy)benzamide in 100 ml. of dichloromethane isadded 9.48 g. (120 mmole) of pyridine followed by 6.48 g. (60 mmole) oftrimethylchlorosilane. After stirring 1 hour, 4.01 g. (30 mmole) ofethyl oxalyl chloride is added. The resulting solution is stirred for 48hours, poured into dilute hydrochloric acid and the organic phase isseparated. The aqueous layer is extracted with methylene chloride, thecombined organic layers are washed with dilute hydrochloric acid anddried and evaporated. The residue is recrystallized from ethylacetate-hexane to give 7.7 g. of product, mp. 146°-148° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₆ : Calc'd: C, 52.70; H, 5.44; N,9.46; Found: C, 52.52; H, 5.42; N, 9.34.

EXAMPLE 77 3-Benzyloxy-2-carbamoylphenyl)oxamic acid ethyl ester. 55/22at 25 mg/kg

2-Amino-6-benzyloxybenzamide is treated with ethyl oxalyl chloride inthe usual manner to give the ester, mp. 151°-153° C.

Elemental Analysis for C₁₈ H₁₈ N₂ O₅ : Calc'd: C, 63.15; H, 5.30; N,8.18; Found: C, 63.31; H, 5.47; N, 8.36.

2-Amino-6-benzyloxybenzamide is prepared by the Raney nickel reductionof 2-benzyloxy-6-nitrobenzonitrile (E. Cortes & F. Walls, Boll Inst.Quim. Univ. Nach. Auton. Mex. 16, 71 (1964; C.A. 63, 533c (1965) in theusual manner; m.p. 158°-160° C.

Elemental Analysis for C₁₄ H₁₄ N₂ O₂ : Calc'd: C, 69.40; H, 5.83; N,11.56; Found: C, 69.25; H, 6.10; N, 11.69.

EXAMPLE 78 N-Hydroxy-N'-phenyloxamide. 92

The title compound is prepared by the method of Dimroth et al., Chem.Ber. 39, 3917; m.p. 165°-167° C.

Elemental Analysis for C₈ H₈ N₂ O₃ Calc'd: C, 53.33; H, 4.48; N, 15.55;Found: C, 53.30; N, 4.48; N, 15.07.

EXAMPLE 79 (4-Chlorophenyl)oxamic acid ethyl ester. 64

The title compound was prepared by the method disclosed in Farmaco, Ed.Sci. 22(9), 717-734 (1967); m.p. 149°-152° C.

Elemental analysis for C₁₀ H₁₀ NO₃ Cl Calc'd: C, 52.76; H, 4.43; N,6.15; Found: C, 52.71; H, 4.40; N, 6.19.

EXAMPLE 80 (4-Dimethylaminophenyl)oxamic acid ethyl ester. 100/16 at 25mg/kg per os.

The title compound was prepared by the method disclosed in Chem. Abstr.,72, P. 12413 M (1970); m.p. 166°-170° C.

Elemental analysis for C₁₂ H₁₆ N₂ O₃ ·HCl Calc'd: C, 52.84; H, 6.28; N.10.27; Cl; 13.00; Found: C, 52.93; H, 6.28; N, 10.27; Cl, 11.98.

EXAMPLE 81 (3-Cyano-2-pyridyl)oxamic acid ethyl ester. 100

To a solution of 5.95 g. (0.05 mole) of 2-aminonicotinonitrile (E. C.Taylor and A. J. Crovetti, J. Org. Chem. 19, 1633 (1954) is 150 ml. ofmethylenechloride and 7.9 g. (0.1 mole) of pyridine is slowly added 6.8g. (0.05 mole) of ethyloxalyl chloride. After the addition the reactionis stirred for one hour, evaporated to dryness and 5 ml. of water isadded. The mixture is filtered and the crude product is recrystallizedfrom methylene chloride-diethyl ether to yield 2.9 g. of pure product,m.p. 95°-97° C.

Elemental Analysis for C₁₀ H₉ N₃ O₃ ; Calc'd: C, 54.79; H, 4.14; N,19.17; Found: C, 54.59; H, 4.05; N, 18.89.

EXAMPLE 82 [2-(Aminocarbonyl)-3-(dimethylamino)phenyl]oxamic acid ethylester. 54/21 at 25 mg/kg per os.

This is prepared from 2-amino-6-dimethylaminobenzamide and ethyl oxalylchloride in the usual manner, m.p. 133°-135° C.

Elemental analysis for C₁₃ H₁₇ N₃ O₄ Calc'd: C, 55.90; H, 6.14; N,15.05; Found: C, 56.04; H, 6.21; N, 14.54.

2-Amino-6-dimethylamino benzamide is prepared by the Raney nickelreduction of 2-dimethylamino-6-nitrobenzonitrile following the procedurepresented in Example 77.

2-Dimethylamino-6-nitrobenzonitrile is prepared from molar equivalentsof 2,6-dinitrobenzonitrile and dimethylamine hydrochloride indimethylformamide in the presence of aqueous KOH.

EXAMPLE 83 [2-Carbamoyl-3-(methylthio)phenyl]oxamic acid ethyl ester.98/25 at 25 mg/kg per os.

This is prepared by ethyloxalation of 2-amino-6(methylthio) benzamide,m.p. 168°-170° C.

Elemental Analysis for C₁₂ H₁₄ N₂ O₄ S Calc'd: C, 51.05; H, 5.00; N,9.92; S, 11.36; Found: C, 51.06; H, 4.92; N, 10.08; S, 11.65.

2-Amino-6-(methylthio) benzamide is prepared by Raney nickel reductionof 2-(methylthio)-6-nitrobenzonitrile which is prepared from2,6-dinitrobenzonitrile and methylmercaptan following the procedure setforth in Example 75.

EXAMPLE 84 [(2-Aminocarbonyl-3-methylsulfinylphenyl)amino]oxoacetic acidethyl ester 44/23 at 25 mg/kg per os.

A mixture of 2.0 g. of [2-carbamoyl-3-(methylthio)phenyl]oxamic acidethyl ester and 1.44 g. of m-chloroperoxybenzoic acid in 200 ml. ofmethylene chloride is stirred for 2 hours. 0.6 g. of sodium bicarbonatein 20 ml. of water is added, the methylene chloride layer is separated,dried and evaporated. The residue is recrystallized from ethanoldiethylether, m.p. 164°-166° C.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ S Calc'd: C, 48.31; H, 4.73; N,9.39; S, 10.74; Found: C, 48.15; H, 4.56; N, 9.26; S, 10.38.

What is claimed is:
 1. A process for preventing the release ofpharmacological mediators from an immediate hypersensitivity reactionbetween reaginic type antibodies and an antigen, thereby preventing thesymptoms manifest in bronchial asthma, seasonal pollinosis, allergicrhinitis, urticaria, allergic conjunctivitis, food allergy, andanaphylactoid reactions of a sensitized animal, which comprisesprophylactically administering to said animal an effective amount of acompound of the formula: ##STR12## in which B is a member selected fromthe group consisting of --OH, lower alkoxy, --NH₂, --NHOH, loweralkylamino, cyclohexyloxy and phenoxy.
 2. The process of claim 1 inwhich B is lower alkoxy.
 3. The process of claim 2 in which B is ethoxy.4. A pharmaceutical composition a lower alkyl ester of (2-thiazolyl)oxamic acid in an amount sufficient to suppress allergic manifestationsof atopic immediate sensitivity in a warm-blooded animal and apharmaceutically acceptable carrier.